Recent studies have shown that many children with mental retardation and epilepsy have abnormalities of migration of neurons to the developing cerebral cortex, resulting in cortical dysplasia. Almost nothing is known about how neurons migrate, or about the molecular mechanism regulating this migration. Additionally, one of the major hurdles in neuronal transplantation or regeneration following damage is poor neuronal migration into target areas which may be overcome through approaches derived from a better understanding of how neurons migrate. One not uncommon inherited cause of severe mental retardation and epilepsy in humans is classical lissencephaly, defined by a lack of cortical gyri and sulci formation and apparently due to a failure of proper neuronal migration. Mutations in either of two genes, doublecortin (DCX) or lissencephaly-1 (LIS1) produces nearly identical lissencephaly in humans and are therefore required for proper neuronal migration. A mutation in the cdk5 gene in mouse also leads to a defect in neuronal migration that is strikingly similar to human lissencephaly. The central hypothesis of this application is that these common mutant phenotypes suggest that there may be interactions between the encoded proteins. The predicted DCX and LS1 proteins are entirely novel, suggesting they may help define novel molecular mechanisms of neuronal migration, and both were previously shown to function as microtubule-associated proteins that are localized around the nucleus. The cdk5 gene is a serine-threonine kinase that phosphorylates some cytoskeletal proteins. However, the underlying defect that is responsible for impaired migration when these genes are mutated is unknown. Additionally, despite the very similar mutant phenotypes, it is untested whether these proteins act in a common pathway or directly interact to mediate their effect. Therefore the aims of this proposal are: 1. Determine whether there are genetic or physical interactions between DCX and LIS1 2. Determine whether DCX and LIS1 function to regulate nuclear movement during neuronal migration. 3. Determine whether the function of DCX in neuronal migration is regulated by cdk5